Severe combined immune deficiency (SCID) includes a variety of genetic defects characterized by severe numerical and functional defects of T lymphocytes, variably associated with defects of B and NK lymphocytes. Differences exist between mice and humans with mutations in orthologue SCID- associated genes. Moreover, for some forms of SCID no animal models are currently available. Finally, SCID have offered proof of principle that gene therapy can cure human diseases; however, leukemic proliferation due to insertional mutagenesis has been reported in 5 SCID patients treated by gene therapy. Altogether, these notions emphasize the importance of studying human models to gain insights into pathological human T cell development and to develop novel and safer approaches to gene therapy. Co-culture of human hematopoietic stem cells (HSCs) with mouse OP9 stromal cells engineered to express the Notch1 ligands Delta-like 1 (Dll1) or Delta-like 4 (Dll4) has been used to study T cell differentiation. Moreover, severely immunodeficient mice can serve as an in vivo system to study T cell development from human HSCs. However, these approaches can be hardly applied to the study of human SCID, given the rarity of this condition that limits access to freshly isolated HSCs from the patients. Induced pluripotent stem cells (iPSCs) represent a novel tool for disease modeling and correction and may be used to overcome technical and feasibility barriers that have so far hampered the study of T cell development in human SCID. We have assembled a team of investigators with specific and complementary expertise in immunodeficiency, iPSC biology, T cell development and integration site analysis upon gene transfer. We have created a large repository of fibroblast cell lines from patients with various forms of SCID. We now intend to generate iPSCs from these patients. We will characterize the stemness and pluripotency profile and verify genetic integrity of patient-derived iPSCs. To model SCID, we will differentiate iPSCs into T lymphocytes both in vitro and in vivo. We also intend to use patient-derived iPSCs as a platform to explore the efficacy and safety of self-inactivating lentiviral vectors in the correction of various forms of SCID both in vitro and in viv in immunodeficient mice. We anticipate that SCID patients-derived iPSCs will represent a novel and robust platform to study human T cell development and for preclinical assessment of efficacy and safety of gene therapy for these diseases.